Homogeneous preformulations containing high concentrations of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations

ABSTRACT

A homogeneous steroid-containing preformulation for production of solid and semi-solid pharmaceutical preparations containing a uniform constant dosage of at least one steroid in a range from 0.001 to 1 percent by weight is described. This steroid-containing preformulation contains of from 0.001 to 50 percent by weight of the at least one steroid. The homogeneous steroid-containing preformulation is made by a method including dissolving the at least one steroid in a solvent to form a dispersant; dispersing an adjuvant consisting of adjuvant particles in the dispersant in a mass ratio of the adjuvant to the at least one steroid of  1:1  to 1000:1 to form a suspension; and creating a spray-mist of the suspension so as to evaporate and remove the solvent from the suspension and thus to form a dried particulate which includes steroid-containing particles. The droplets in the spray mist have a droplet diameter greater than a mean diameter of the adjuvant particles. The maximum particle size of the dried particulate forming the steroid-containing preformulation is increased by less than 30 percent in comparison to an average particle size of the adjuvant particles.

This application is a 371 of PCT/DE97/02915 filed Dec. 15, 1997

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to homogeneous preformulations containing highconcentration of steroids, for producing low-dose solid and semi-solidpharmaceutical preparations having a concentration content of 0.001 to 1weight percent of steroid.

2. Prior Art

The invention also relates to a method for producing the homogeneouspreformulations, containing steroids in high concentration, for theclaimed low-dose solid and semi-solid pharmaceutical preparation.

It is known that the homogeneous distribution of active ingredients isan essential prerequisite for the reliable effect of a medication.

The problem of homogeneous active ingredient distribution arisesespecially in single-dose solid and semi-solid forms of preparation inwhich the active ingredient is not in dissolved form, such as intablets, lozenges, capsules and suppositories.

The prerequisite for the homogeneous distribution of active ingredientsin the single-dose forms of medication is on the one hand a uniformdistribution of the active ingredient in the basic mixture orpreformulation and on the other the preservation of this distributionduring further processing. Nonhomogeneities in the mixture of activeingredients and adjuvants and inaccuracies in further processing areadded together and lead to fluctuations in dosage in solid andsemi-solid single dose forms of medication.

In high-dose preparations, as a rule no serious mixing nonhomogeneitiesoccur.

In low-dose forms of medication, the primary problem is to furnish asufficiently homogeneous distribution, which is stable against demixing,of the very low mass of active ingredient in proportion to the mass ofthe pharmaceutical adjuvants.

From the professional and patent literature, low-dose solid andsemi-solid preparations containing steroids are known; thepreformulations are produced by means of dry and moist granulationtechnologies or dry mixing processes.

M. Dittgen, H. Kala et. al., for instance, in “Zur pharmazeutischenTechnologie der Granulierung” [On the pharmaceutical technology ofgranulation], Pharmazie 35, 4, pages 237 to 249, 1980, describe suchgranulation technologies.

It is problematic by means of the mixing process to achieve good contentuniformity while avoiding demixing and sizing effects, for instance fromdefluidizing and outgassing of fine active ingredient particles from thefluidized bed.

Formulations produced by these technologies have the disadvantages of

the use of micronized active ingredients and the attendant necessity ofone additional process step;

derived from this the possibility of recrystallization and clumping byway of the active surfaces of the active ingredient particles and theattendant negative effects on homogeneity and release properties.

In a special form of the fluidized bed-spray granulation process, theuse of micronized active ingredients is circumvented by dissolving theactive ingredient in an organic solvent at high dilution and spraying itonto a large-particle adjuvant moving in a fluidized bed and granulatingit by building on that structure.

The disadvantages of the formulations produced by this method are:

the occurrence of deviations from the desired steroid content byoutgassing of fine steroidal abrasion from the fluidized bed;

the fact that because of the long dwell times in the production process,undesired decomposition processes can occur in thermally unstable activeingredients.

One disadvantage of the method that should not be underestimated is thatlarge quantities of solvent are in the final steps of the galenicpreparation, which requires major effort and expense for equipment andsafety technology (explosion proofing together with rendering nitrogeninert).

In European patent disclosure EP 0 503 521, it is described that adirect-tabletable pharmaceutical preparation is attained by dry mixingof micronized steroids with certain excipients (spray-dried lactose).

This proves to have the following disadvantages:

Only selected excipients have the requisite adsorptive properties;

The loading capacity of the surfaces is only very limited;

once again, micronized active ingredients are used, which have thedisadvantage of recrystallization and clumping along the active surfacesof the active ingredient particles and the attendant negative effects onhomogeneity and release properties.

M. Dekker, in “The spray drying of pharmaceuticals”, Drug Developmentand Industrial Pharmacy”, 18 (11 & 12) pages 1169 through 1206, 1992,and

E. Nürnberg, in “Darstellung und Eigenschaften pharmazeutisch relevanterSprühtrocknungsprodukte” [Characterization and properties ofpharmaceutically relevant spray drying products], Acta PharmazeuticaTechnologica, 26(1), pages 40 to 67, 1980 describe the use of spraydrying technology for the galenic formulation of pharmaceutical activeingredients, including steroids.

With the spray drying, primarily retardant effects or effects thatimprove solubility and stability are attained by way of activeingredient imbedding or microencapsulations (for instance in polymericadjuvants) or inclusion complexes (in cyclodextrins).

According to J. Cooper and J. E. Rees, “Tableting research andtechnology” J. Pharm. Sci. 61 (1972) pages 1551 to 1555, the spraydrying can be used

for coating medication particles with protective casings and formodifying the physical properties of the active ingredients andadjuvants, with the goal of making their further processing (such astablets) easier.

According to H. Kala et.al., “The use of spray drying in pharmacy”,Pharmazie, 34, No. 12 (1979) pages 779 to 784, the use of spray dryingfor attaining certain properties in active ingredients and adjuvantsthat go beyond simple drying and simultaneous micronization isfundamentally known.

For example, metastable medication modifications or amorphous activeingredients can be produced in standardized fashion, in order to improvethe speed of dissolution or to preclude uncertainty factors dictated bythe existence of various crystal modifications.

In this connection, spray imbedding in various adjuvants and spraydrying of suspensions of a solution of medication and insoluble adjuvant(celluloses) are mentioned in particular.

H. Kala et.al. also mention that spray products (adjuvants as drybinders, active ingredients, and combinations) in the form of spherical,free-flowing particles have already been used for direct tableting.

M. Dekker, in “The spray drying of pharmaceuticals”, Drug Developmentand Industrial Pharmacy, 18 (11 & 12) pages 1169 through 1206, 1992,mentions that fine, free-flowing adjuvant granulates (fillers, binders,explosives, pigments) for direct tableting can be produced by spraydrying.

The goal of this spray granulation process is to attain more favorableprocessing properties, which however as a rule are associated with anincreased particle size, for direct tableting.

The disadvantage of these technologies with a view to direct productionof low-dose pharmaceutical preparations is as follows:

because of the large particle size of these granulates, the requisitecontent uniformity does not always exist through subsequent mixing;

the spray granulation of the necessarily highly dilute steroid solutionsor suspensions is very complicated and expensive, because of the largevolumes involved.

SUMMARY OF THE INVENTION

Homogeneous preformulations containing high concentration of steroids,for producing low-dose solid and semi-solid pharmaceutical preparationshaving a concentration content of 0.001 to 1 weight percent of steroidsand the production of a homogeneous preformulation, containing steroidsin high concentration, for low-dose solid and semi-solid pharmaceuticalpreparation with a concentration content of 0.001 to one weight percentof steroid by means of spray drying, in which in a conventional drymixing process while avoiding the above disadvantages the preformulationcan be processed into a direct-tabletable pharmaceutical preparation,are not described in the patent and professional literature.

The object of the invention is to furnish steroid-containingpreformulations that assure the production of low-dose solid andsemi-solid pharmaceutical preparations with a concentration content of0.001 to 1 weight percent of steroid with good homogeneity of thesteroid adjuvant, along with good stability of the active ingredientdistribution in the pharmaceutical preparation. This object is attainedaccording to the invention by furnishing homogeneous preformulationscontaining high concentration of steroids, for producing low-dose solidand semi-solid pharmaceutical preparations having a concentrationcontent of 0.001 to 1 weight percent of steroid, obtained by evaporationof the dispersant, containing the steroidal active ingredient, from asuspension with dispersed pharmaceutically conventional adjuvant, inwhich a spray mist is created, whose mean droplet diameter is greaterthan the mean diameter of the adjuvant particles, and the maximumparticle size of the dried particles of the steroid containingpreformulation is increased by less than 30 percent in comparison to theparticle size of the adjuvant.

It proves to be especially advantageous if the maximum particle size ofthe dried particles of the dried particles of the steroid-containingpreformulation is increased by less than 10% in comparison with theparticle size of the adjuvant.

It is also especially advantageous that the concentration of thesteroidal active ingredient in the steroid-containing preformulationamounts to from 5 to 30 weight percent.

According to the invention the method of making the homogeneoussteroid-containing preformulation comprises the steps of:

a) dissolving steroid or steroid ingredients in a solvent to form adispersant;

b) dispersing an adjuvant consisting of adjuvant particles in thedispersant in a mass ratio of adjuvant to the steroid or steroidingredients of 1:1 to 1000:1 to form a suspension; and

c) creating a spray-mist of the suspension so as to evaporate and removethe solvent from the suspension and thus to form a dried particulatecomprising a plurality of steroid-containing particles, the spray mistcomprising a plurality of droplets having a droplet diameter greaterthan a mean diameter of the adjuvant particles;

wherein a maximum particle size of the dried particulate comprising thesteroid-containing preformulation is increased by less than 30 percentin comparison to an average particle size of the adjuvant particles.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As the sexual hormone, one component from the group comprisingestrogens, gestagens and antigestagens, or a component that quicklysplits off the above active ingredients after administration, ispreferably used.

The method of the invention for producing the homogeneouspreformulations containing steroids in high concentration will now bedescribed in further detail:

The steroidal active ingredient or active ingredients are dissolved in asuitable solvent, such as ethanol.

Stability-improving adjuvants that speed up resorption or modify therelease kinetics are optionally added. Next, the adjuvant is suspendedwith a mass ratio to the dissolved steroid of 1:1 to 100,000:1. A rangeof from 2:1 to 20:1 proves to be especially advantageous for the method.As adjuvants, alpha-lactose monohydrate, microcrystalline cellulose orinorganic calcium salts, preferably in micronized form, can be used.

Next, the suspension is spray-dried for the sake of gentle, rapidremoval of the solvent and stable and finely dispersed distribution ofthe active ingredient on the surface of the adjuvant.

It is especially notable that from the sprayed suspension, activeingredient particles and adjuvant particles are not dried side by side.By a selection of the process conditions in the spraying process, theactive ingredient can be bonded virtually completely and materially tothe adjuvant.

An essential role is played by the particle size distribution of theactive ingredient, the solid concentration of the suspension, the activeingredient concentration of the solution, and the droplet sizedistribution in the spray mist, which in turn is substantially affectedby the effect of the atomizer device (nozzle or disk) and by theviscosity of the solution.

The spray process should be conducted such that the mean dropletdiameter in the spray mist is greater than the mean diameter of theadjuvant particles, but on the other hand is not so great that asubstantial increase in particle size occurs from granulation.

The process conditions should be adjusted specifically to suit the spraydrying equipment used and the system of substances involved.

The steroidal preformulations thus produced are mixed dry in a suitablemixture together with other direct-tabletable adjuvants, such asTablettose, Ludipres, Emcompress, or Avicel, and then filled into hardgelatin capsules or in the form of an oily suspension in soft gelatincapsules, or tableted in the usual way. The tablets are made intolozenges or coated in aqueous or organic fashion, together with theusual, known adjuvants.

With the invention, homogeneous preformulations containing highconcentration of steroids, for producing low-dose solid and semi-solidpharmaceutical preparations having a concentration content of 0.001 to 1weight percent of steroid are furnished, which are distinguished bytheir homogeneity and stability to demixing, and the steroidal activeingredient is contained in finely dispersed form, materially bonded tothe adjuvant.

Surprisingly, it has been found that steroidal preformulations of thiskind can be processed in a suitable mixture in dry fashion along withthe usual tableting adjuvants without problems to produce low-dosepharmaceutical preparations with very good, stable active ingredienthomogeneity.

Testing for uniformity of the content of the single-dose forms ofmedication is done as prescribed by PhEur and DAB 9.

Testing is based on the determination of the medication content of anumber of single-dose units in order to ascertain whether the singlecontent is within the defined limits, referred to the average content ofa model specimen.

Execution:

In ten units extracted arbitrarily by the random sample process, themedication content is determined individually, with the aid of asuitable analytic method.

Table 1 shows the properties of tablets whose preformulation wasproduced by exemplary embodiment 2.

Tablets Containing 30 μg of Ethinyl Estradiol

Content uniformity according to Ph. Eur./DAB: 29 μg Relative standarddeviation (S rel): 2.26%

The homogeneity is proved in accordance with the Content UniformityTest—to be employed with a proportion of active ingredient of 50 mg andless per individual dose.

The following was also demonstrated:

Release of active ingredient (n = 6) 82% after 45 min Requirement: >=75%after 45 min S rel: 1.53% Hardness (n = 10): 35.6 N Uniformity of thetablet composition per attained Ph. Eur./DAB: Mean tablet mass (n =100): 50.7 mg S rel: 2.10% Max: 54.0 mg Min: 49.0 mg

Table 2 shows the properties of tablets whose preformulation is producedin accordance with exemplary embodiment 3.

Tablets Containing 250 μg of Sulfamate Steroid

Content uniformity according to Ph. Eur./DAB: 253 μg Relative standarddeviation (S rel): 1.28%

The homogeneity is proved in accordance with the Content uniformitytest—to be employed with a proportion of active ingredient of 50 mg andless per individual dose.

The following was also demonstrated:

Release of active ingredient (n = 6) 101.0% after 45 minRequirement: >=75% after 45 min S. rel: 3.4% Decomposition time: 1:19min Hardness (n = 10): 36.7 N Uniformity of the tablet composition perattained Ph. Eur./DAB: Mean tablet mass (n = 100): 51.9 mg S rel: 0.86%Max: 53.0 mg Min: 51.0 mg

Table 1 and Table 2 show that the steroidal preformulations of theinvention can be processed to make low-dose pharmaceutical preparationswith very good, stable active ingredient homogeneity.

The advantages of the method of the invention for producing thehomogeneous preformulations of the invention that contain steroids inhigh concentration are:

Very good, stable active ingredient homogeneity in the pharmaceuticalpreparation for tableting.

The limit particle size of the preformulation, which is important forsubsequent mixing processes, is defined by the choice of the adjuvantparticle size, since this particle size is increased onlyinsignificantly (see Examples 1-3 and Tables 3-5) by the spraying on ofthe active ingredient.

Nonhomogeneities and demixing or sizing effects during the subsequentmixing process are thus avoided.

The advantageous galenic properties of the adjuvant are transferred tothe preformulation, and the solid properties of the active ingredientare stabilized.

Clumping and attendant changes in activity, as are often observed inmicronized steroids, did not occur.

The use of micronized steroids can be dispensed with. This means thatone complicated process step can be eliminated. Micronized steroidactive ingredients, such as desogestrel, often have a tendency to laterrecrystallization and clumping effects, which are deleterious to theactive ingredient homogeneity and release.

At the same time, the influence of crystallization in producing theactive ingredient, or in other words the often complicated definitionand validation of the crystal structure and crystallinity, is averagedout.

The preformulations are stable to demixing and can be stored.

By the spray drying of the suspension droplets (adjuvant particlessheathed with active ingredient solution), which are finely distributedin a drying gas, via a nozzle or atomizer disk, a material and finelydispersed bonding of the active ingredient with the adjuvant surface isattained by a rapid evaporation of the solvent. As a result theadsorptive properties of the adjuvant, which in the prior art aredecisive for dry mixing with micronized steroids and which substantiallyrestrict the selection of adjuvants, are of only secondary importance.

The loading of the adjuvant with active ingredients can be substantiallygreater than in mechanical mixing of the adjuvant with micronizedsteroids.

A loading ratio of 1 (gram of steroid to gram of adjuvant) can beattained.

The attainable loading is dependent only on the solubility of thesteroid in the solvent used, on the droplet size (spray conditions), andon the particle size of the adjuvant.

In common with the dissolved steroid and suspended adjuvant, otheradjuvants that improve stability, speed up resorption or modify therelease kinetics and that can be present in dissolved or suspended formcan be spray dried.

Incorporating these adjuvants already in the preformulation stage makesthe mixing stage of the pharmaceutical final formulation easier extendsthe above-discussed advantages of spray drying with regard to thesteroid distribution on the adjuvant to these adjuvants as well.

It is also possible, for instance by using suitable soluble adjuvants,to embed the active ingredient in molecularly dispersed form in theadjuvant sheath and thus to speed up or slow down the release or toprotect the active ingredient against the environment.

By way of the spray process, more galenic possibilities are thus openedup than by way of dry mixing of micronized steroids and adjuvants.

The spray drying process, since the evaporation of the solvent takesplace within fractions of a second, is an extremely gentle processprecisely for thermally vulnerable steroids (such as sulfamatesteroids).

The above-discussed advantages allow the flexible production ofsteroidal preformulations with specific galenic properties as for thepharmaceutical final formulation of the tablet composition.

The galenic complication and the pharmaceutical technology for the finalformulation are drastically reduced and simplified.

The preformulations produced in a preliminary step, heavily loaded withsteroid and thus low in quantity, can be processed without problems bythe dry mixing process to produce very homogeneous tablets with theusual tableting adjuvants.

The production of the preformulations of the invention will be describedin further detail in the ensuing examples, but is not limited by them.

EXAMPLE 1

25 g of desogestrel are dissolved in 562 g of ethanol (96%, DAB) and 63g of water.

To the clear solution, 125 g of lactose monohydrate (Sorbolac 400,Meggle) are added while stirring.

The suspension is dried with a dryer with a dual-substance nozzle in theparallel-flow process.

conditions:

Air inlet temperature: 115° C. Air outlet temperature: 66° C. Inflow ofthe suspension: 10 ml/min Spray pressure (N2): 2.5 bar (ü) Nozzle: 0.7mm Drying air: 350 L/min

The dry product is precipitated using a cyclone.

Particle Size Analysis:

Lactose used Preformulation μm μm ×10 1.57 3.37 ×50 7.94 10.76 ×90 24.1826.75

The figures given are statements pertaining to the maximum particlesize. For instance, ×90 states that 90% of the lactose used and of thepreformulation are smaller in their particle size than 24.18 and 26.75μm, respectively.

EXAMPLE 2

12 g of ethinyl estradiol are dissolved in 180 g of ethanol (96%, DAB).

To the clear solution, 48 g of lactose monohydrate (Sorbolac 400,Meggle) are added while stirring.

The suspension is dried with a dryer with a dual-substance nozzle in theparallel-flow process.

Air inlet temperature: 140° C. Air outlet temperature: 74° C. Inflow ofthe suspension: 10 ml/min Spray pressure (N2): 1.3 bar (ü) Nozzle: 0.7mm Drying air: 300 L/min

The dry product is precipitated using a cyclone.

Particle Size Analysis:

Lactose used Preformulation μm μm ×10 1.34 1.69 ×50 6.10 7.05 ×90 18.0220.36

EXAMPLE 3

6 g of a sulfamate steroid are dissolved in 240 g of ethanol (96%, DAB).

To the clear solution, 22 g of lactose monohydrate (Sorbolac 400,Meggle) are added while stirring.

The suspension is dried with a dryer with a dual-substance nozzle in theparallel-flow process.

Air inlet temperature: 120° C. Air outlet temperature: 62° C. Inflow ofthe suspension: 10 ml/min Spray pressure (N2): 1.3 bar (ü) Nozzle: 0.7mm Drying air: 300 L/min

The dry product is precipitated using a cyclone.

Particle Size Analysis:

Lactose used Preformulation μm μm ×10 1.34 1.43 ×50 6.10 6.40 ×90 18.0219.86

The particle size analyses show that by the choice of the adjuvantparticle size, the limit particle size of the preformulation which isimportant for subsequent mixing processes is defined, since thisparticle size is increased only insignificantly by the spraying on ofthe active ingredient.

Nonhomogeneities and demixing and sizing effects during the subsequentmixing process are thus avoided.

What is claimed is:
 1. A method of producing a homogeneoussteroid-containing preformulation containing at least one steroid in aconcentration of from 0.001 to 50 percent by weight, said preformulationcomprising a starting material for production of solid and semi-solidpharmaceutical preparations containing a uniform constant dosage of saidat least one steroid, said dosage of said at least one steroid being ina range from 0.001 to 1 percent by weight, said method comprising thesteps of: a) dissolving the at least one steroid in a solvent to form adispersant; b) dispersing an adjuvant consisting of adjuvant particlesin said dispersant in a mass ratio of the adjuvant to the at least onesteroid of 1:1 to 1000:1 to form a suspension; and c) creating aspray-mist of the suspension so as to evaporate and remove said solventfrom said suspension and thus form a dried particulate comprising aplurality of steroid-containing particles, said spray mist comprising aplurality of droplets having a droplet diameter greater than a meandiameter of said adjuvant particles; wherein a maximum particle size ofthe dried particulate comprising the steroid-containing preformulationis increased by less than 30 percent in comparison to an averageparticle size of said adjuvant particles.
 2. The method as defined inclaim 1, wherein said mass ratio of said adjuvant to said at least onesteroid is from 2:1 to 20:1.
 3. The method as defined in claim 1,wherein said maximum particle size of said dried particulate isincreased by less than 10% in comparison to said average particle sizeof said adjuvant particles.
 4. The method as defined in claim 1, whereinsaid steroid-containing preformulation includes from 5 to 30 percent byweight of said at least one steroid.
 5. The method as defined in claim1, wherein said adjuvant is selected from the group consisting ofalpha-lactose monohydrate, microcrystalline cellulose and inorganiccalcium salts.
 6. The method as defined in claim 1, wherein said solventis ethanol or a mixture of ethanol and water.